Project Summary/Abstract A general understanding of the metabolic needs of photoreceptors could lead to broadly applicable therapeutic strategies to treat retinas stressed by diverse genetic and environmental factors. With that in mind, we have been investigating the fundamental nature of energy metabolism in the retina and the retinal pigment epithelium (RPE). Photoreceptor metabolism is limited by the availability of nutrients from the RPE. Evidence indicates that the retina and RPE function together as a network of metabolically specialized and interdependent cells. We hypothesize that a deficiency in any component of that network could lead to retinal degeneration as part of the failure of the entire metabolic ecosystem. Our recent findings support this hypothesis. We have proposed a model in which the flow of glucose from the choroidal blood through the RPE to the retina is enhanced by lactate produced by glycolysis in photoreceptors. Lactate not only fuels the RPE, but it also can influence the differentiation state of RPE cells. These observations are the basis for the specific aims of this proposal. The first aim will explore ways to enhance the flow of glucose across the RPE. The second aim will investigate how lactate influences differentiation of RPE cells. This project will identify ways to enhance the flow of glucose across the RPE to the retina. Our findings can be used to design therapeutic approaches that make photoreceptors in an eye more robust and resistant to genetic and environmental factors that normally would cause photoreceptor degeneration. .